Pharmaceutically useful (+)-1-(3-dimethylaminopropyl)-1-(4&#39;-fluorophenyl)-1,3-dihydroiso benzofuran-5-carbonitrile and non-toxic acid addition salts thereof

ABSTRACT

The two enantiomers of the anti-depressant drug of the formula I   &lt;IMAGE&gt;   are disclosed. Methods for resolving intermediates and their [steroselective] stereoselective conversion to a corresponding [enatiomer] enantiomer of I are also disclosed.

The present invention relates to the two novel enantiomers of theantidepressant drug1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-.[.dihydroisobenzofuran.]..Iadd.dihydroisobenzofuran.Iaddend.-b 5-carbonitrile (citalopram) of thefollowing formula I: ##STR2## and to the use of these enantiomers asantidepressant compounds as well as the possible use as geriatrics or inthe cure of obesity or alcoholism.

This invention also includes pharmaceutically acceptable salts of theenantiomers of compound I formed with non-toxic organic or inorganicacids. Such salts are easily prepared by methods known to the art. Thebase is reacted with either the calculated amount of organic orinorganic acid in an aqueous miscible solvent, such as acetone orethanol, with isolation of the salt by concentration and cooling or anexcess of the acid in aqeuous immiscible solvent, such as ethyl ether,ethyl acetate or .[.dicloromethane.]. .Iadd.dichloromethane.Iaddend.,with the desired salt separating directly. Exemplary of such organic.].salt.]. .Iadd.salts .Iaddend.are those with maleic, fumaric, benzoic,ascorbic, pamoic, succinic, oxalic, salicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, citric, gluconic, lactic,malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic,itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic andtheophylline acetic acid, as well as the 8-halotheophyllines, forexample 8-bromotheophylline.

Exemplary of such inorganic salts are those with hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course,these salts may also be prepared by the conventional method of doubledecomposition of appropriate salts, which is well-known to the art.

Furthermore it was found that non-hygroscopic acid addition salts mightbe obtained by .[.conventinal.]. .Iadd.conventional .Iaddend.freezedrying techniques from water solutions of appropriate salts of the abovementioned kinds.

The invention is also concerned with a method to resolve theintermediate racemate and to produce the individual isomers of Itherefrom.

BACKGROUND OF THE INVENTION

Citalopram, which has been disclosed in e.g. U.S. Pat. No. 4,136,193,has proven to be an efficient antidepressant compound in man (Ref.: A.Gravem et. al., Acta pysychiat. Scan., No. 75, p. 478-486 (1987). Allwork in the development of this compound has been made with theracemate. Citalopram has been shown pharmacologically to be a veryselective inhibitor of 5-HT reuptake. Previous attempts to crystallizediastereomeric salts of citalopram enantiomers have failed.

SUMMARY OF THE INVENTION

Surprisingly, it has now proven possible to resolve the intermediate.[.4-(4-dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benzonitrile.]..Iadd.4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile.Iaddend.,II, into its enantiomers and finally in a stereoselective way to convertthese enantiomers to the corresponding citalopram enantiomers. Likewise,monoesters of II formed by optically active carboxylic acids could beseparated into the corresponding diastereomers and subsequentlyconverted directly into citalopram enantiomers in a steroselectiveringclosure reaction. The intermediate diol, II, has been disclosed ine.g. U.S. Pat. No. 4,650,884 as a racemic mixture. ##STR3##

The enantiomers of the intermediate of formula II as well as monoestersfall likewise within the scope of the present invention.

Furthermore, it was shown to our surprise that almost the entire 5-HTuptake inhibition resided in the (+)-citalopram enantiomer.

The present invention also includes a new method of synthesizing I fromthe diol compound II by esterification of the primary alcohol group intoa labile ester, which in the presence of a base undergoes spontaneousringclosure to citalopram or, if enantiomerically pure II is esterified,the corresponding citalopram enantiomer is produced with fullyconservation of stereoconfiguration.

According to the invention, II is reacted with:

(a) an enantiomerically pure acid derivative as an acid chloride,anhydride or .[.libile.]. .Iadd.labile .Iaddend.ester as e.g..[.examplified.]. .Iadd.exemplified .Iaddend.in reaction scheme I by(+)- or (-) -α-methoxy-α-trifluoromethylphenylacetyl chloride. Thereaction is preferably performed in an inert organic solvent as e.g.toluene, dichloromethane or tetrahydrofuran. A base (triethylamine,N,N-dimethylaniline, pyridin or the like) is added to neutralizeliberated HCl. The diastereoisomers are subsquently separated by HPLC orfractional crystallization. The thus purified .[.disatereoisomers.]..Iadd.diastereoisomers.Iaddend.are .[.finnaly.]. .Iadd.finally.Iaddend.separately treated with strong base (e.g. alkoxide) in an inertorganic solvent as e.g. toluene, tetrahydrofuran, or dimethoxyethaneyielding the pure citalopram enantiomers respectively. The ringclosurereaction is preferably performed at relatively low temperatures (-20°C.) to room temperature). ##STR4## (b) the enantiomers of an opticallyactive acid successively affording the pure diastereomeric salts.Optically antipodes of tartaric acid, di-benzoyltartaric acid,di-(p-.[.toloyl.]. .Iadd.toluoyl.Iaddend.)tartaric acid,bisnaphthylphosphoric acid, 10-camphorsulphonic acid and the like areconveniently used.

(c) Stereoselective ringclosure of the pure enantiomers of II preparedas in (b) is performed via a labile ester as e.g. methansulfonyl,p-toluenesulfonyl, 10-camphorsulfonyl, trifuoracetyl ortrifluoromethansulfonyl with simultaneous addition of a base(triethylamine, dimethylaniline or pyridin) in an inert organic solventat 0° C. The ringclosure reaction is .[.examplified.]. .Iadd.exemplified.Iaddend.in reaction scheme II: ##STR5##

EXAMPLE 1 Resolution by method (a)

To 11 g of (+)-α-methoxy-α-trifluoromethylacetic acid dissolved in 25 mlof chloroform were added 50 ml of thionylchloride and a few drops ofdimethylformamide. The reaction mixture was refluxed for 2 hours. Excessof thionylchloride was evaporated with toluene leaving the(+)-α-methoxy-α-trifluoromethylacetyl chloride as a liquid. This liquiddiluted with 50 ml of dichloromethane was added dropwise to an icecooled solution of 17 gr of.[.4-(4-dimethylamino-1-(4'-fluorophenyl)-1-hydroxybutyl)-3-(hydroxymethyl)-benzonitrile.]..Iadd.4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile.Iaddend.,II, and 8 ml of triethylamine in 150 ml of dichloromethane. The reactionmixture was further stirred for another hour at room temperature,subsequently washed with brine, dried (MgSO₄) and the solvent evaporatedbelow 30° C. in vacuo affording 29 gr of the ester as a diastereomericmixture. By repeated HPLC purification (eluted with ethylacetate/tetrahydrofuran 9:1 containing 4% of triethylamine) and bycollecting only the 5-10% initial substance in the main peak, 1.1 gr ofenantiomerically pure compound was isolated.

The substance thus isolated was dissolved in dry toluene (50 ml) andadded to a suspension of 0.3 gr of potassium t-butoxide in 20 ml oftoluene at 0° C. The toluene solution was washed with water, dried(MgSO₄) and the solvent evaporated yielding 0.6 gr of(+)-1-(dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrileas an oil. [α]_(D) =+11.81° (c=1, CH₃ OH) (determined with a substancecontaining 10% w/w of methanol). The optical purity was determined by ¹H NMR spectroscopy (CDCL₃ as solvent) (Bruker AC-250 MHz instrument) byaddition of a 10:1 w/w surplus of the chiral reagent(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. Optical purity: 99.6%.

In a totally analogous way the(-)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrilewas synthesized. [α]_(D) =-12.34° (c=1, CH₃ OH) (determined with asubstance containing 10% w/w of methanol). Optical purity: 99.0%.

EXAMPLE 2 Resolution by methods (b) and (c)

To a solution of 85 gr of.[.4-(4-dimethylamino)-1-4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)-benzonitrile.]..Iadd.4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile.Iaddend.,hydrobromide in 500 ml of water were added 200 ml of ice cooled 2M NaOHsolution and 500 ml of ether. The mixture was stirred for 1/2 hour, theether phase separated, dried (MgSO₄) and the ether evaporated. Theremaining oil was dissolved in 400 ml of 2-propanol at 40° C., and 40 grof (+)-di-p-.[.toloyltartaric.]..Iadd.toluoyltartaric .Iaddend.acid (ashydrate) were added under vigorous stirring. After a short whilecrystallization began. After 3 hours of stirring the precipatated saltwas filtered off and dried yielding 29.2 gr (55.1%) of.[.(-)-4-(4-dimethylamino)-1-(4'fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benzonitrile.]..Iadd.(-)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)benzonitrile.Iaddend.,hemi (+)-di-p-.[.toloyltartaric.]. .Iadd.toluoyltartaric .Iaddend.acidsalt. MP: 134°-135° C., [α]_(D) =+10.0° (c=1, CH₃ OH). The filtrate isused below.

To an ice cooled solution of 14 gr of the (-)-isomer from above as abase in 300 ml of dry toluene were added 16 ml of triethylamine, and 3.6ml of methansulfonyl chloride in 20 ml of dry toluene were addeddropwise during 10 minutes. The reaction mixture was further stirred for1/2 hour, washed with brine, dried (MgSO₄) and the solvent evaporated.The title compound was purified by column chromatography affording 8 gof (+)-1-(3-dimethylaminopropyl)-1-(4'-.[.flurophenyl.]..Iadd.fluorophenyl.Iaddend.-1,3-dihydroisobenzofuran-5-carbonitrile.[α]_(D) =+12.33° (c=1, CH₃ OH). The oxalic acid salt of the (+)-isomercrystallized from acetone. MP: 147°-148° C., [α]_(D) =+12.31° (c=1, CH₃OH).

The pamoic acid salt of the (+)-isomer was prepared in the followingmanner: To 1.8 g of the base of the (+)-isomer was added 2 g of pamoicacid in 25 ml of MeOH. The mixture was refluxed for an hour andsubsequently colled to room temperature. The precipitate was filteredoff yielding 3.0 g of the pamoic acid salt. MP: 264°-266° C., [α]_(D)=+13.88° C. (c=1, dimethylformamide).

A 2:1 addition compound of the (+)-isomer with L(+)-tartaric acid wasprepared in the following manner: 4 g of the (+)-isomer as base weredissolved in 100 ml of diethyl ether and extracted into 100 ml of watercontaining 0.8 g of L(+)-tartaric acid by stirring. The organic phasewas separated and discarded. The water-phase was freeze-dried in vacuo(<0.1 mm Hg) for 18 hours leaving 3.8 g of a white powder of the titlecompound. This addition compound was stable and not hygroscopic.

In a corresponding manner as above via the.[.(+)-4-(4-dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benezonitrile.]..Iadd.(+)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile.Iaddend.,hemi (-)-di-(p-toloyl)tartaric acid salt ([α]_(D) =-8.9° (c=1, CH₃ OH))which was converted to the corresponding diol base ([α]_(D) =+61.1°(c=1, CH₃ OH)) and finally ringclosure reaction yielded 10 gr of(-)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile.[α]_(D) =-12.1° (c=1, CH₃ OH).

The oxalic acid salt of the (-)-isomer crystallized from acetone, MP:147°-148° C., [α]_(D) =-12.08° (c=1, CH₃ OH).

EXAMPLE 3 Preparation of citalopram by method (c)

To an ice cooled solution of 28 gr of racemic diol base, II, in 500 mlof dichloromethane were added 32 ml of triethylamine, and 7.5 ml ofmethansulfonyl chloride in 30 ml of dichloromethane were added dropwiseduring a half hour. The reaction mixture was washed with 0.1M NaOHsolution twice, the organic phase separated, dried (MgSO₄) and thesolvent evaporated, leaving 21.5 gr of the title (±)-citalopram as acrystalline base. The thus obtained material was dissolved in a mixtureof 2-propanol and methanol (2:1) and an equivalent amount of gaseous HBrwas introduced. The mixture was left overnight and the precipitatedhydrobromide was filtered off. Yield: 26 gr with MP 184°-186° C.

The enantiomers from Example 1 were tested for their ability to block5-HT reuptake in standard and reliable test method. Results are shown inTable I in comparison with the racemic mixture of citalopram.

5-HTP-POTENTIATION

The test evaluates the ability of the substance to potentiate the effectof 5-HTP, which results in development of 5-HT syndrome (Christensen,Fjalland, Pedersen, Danneskiold-Samsoe and Svendsen; European J.Pharmacol. 41, 153-162, 1977).

Procedure

Each treatment group consists of 3 mice, and two groups are treated withthe highest test dose. A control group only treated with 5-HTP isincluded and a group treated with citalopram 10 mg/kg and 5-HTP is usedas reference for full 5-HT syndrome.

The Route of Administration

30 minutes after the administration of the test substance, the othergroups are given 5-HTP (100 mg/kg) i.v. (injection time 5-10 sec.).After this 5-HTP dose normal, untreated mice remain unaffected, but ifthe animals have been pretreated with a substance, which inhibits theuptake of 5-HT or a 5-HT agonist, a 5-HTP syndrome will occur. Thesymptoms are the same as previously described: (1) excitation, (2)tremor, and (3) abduction of the hind limbs. The animals are observedfor 15 minutes and each animal is given one point for each symptompresent. Again the result is stated in fractions: 0/9, 1/9, . . . 9/9,where 0, 1, . . . , 9 are the number of points per group after the dosein question. The ED₅₀ value is calculated by log-probit analysis.

INHIBITION OF ³ H-SEROTONIN UPTAKE IN RAT BRAIN SYNAPTOSOMES

By this method the inhibition by drugs of the uptake of .[.₃H-serotonin.]. .Iadd.³ H-serotonin .Iaddend.(³ H-5-HT)(10 nm) in ratbrain synaptosomes is determined in vitro. Method and results in Hyttel,Psychopharmacology 1978, 60, 13-18; Hyttel, Prog. Neuro-Psychopharmacol.& Biol. .[.Psychait..]. .Iadd.Psychiat. .Iaddend.1982, 6,277-295; Hyttel& Larsen, Acta pharmacol. tox. 1985, 56, suppl. 1, 146-153. .[.Procedurep.].

.Iadd.Procedure .Iaddend.

Male Wistar (Mol: Wist) rats (125-250 g) are sacrified by decapitationand .[.exanguinated.]. .Iadd.exsanguinated .Iaddend.Brain tissue (minuscerebellum) is gently homogenized (glass teflon homogenizer) in 40 vol(w/v) of ice cold 0.32M of sucrose containing 1 mM of nialamide. The P₂fraction (synaptosomal fraction) is obtained by centrifugation (600 g.10 min and 25000 g. 55 min, 4° C.) and suspended in 800 volumes of amodified Krebs-Ringer-phosphate buffer, pH 7.4.

To 4000 μl of the synaptosomal suspension (5 mg original tissue) on iceare added 100 μl test substance in water. After preincubation at 37° C.for 5 min, 100 μl of ³ H-1-NA (final .[.concnetration.]..Iadd.concentration .Iaddend.10 nM) are added and the samples areincubated for 10 min at 37° C. The incubation is terminated by filteringthe samples under vacuum through .[.Whatmam.]. .Iadd.Whatman.Iaddend.GF/F filters with a wash of 5 ml buffer containing 10 μM ofunlabeled 5-HT. The filters are placed in counting vitals and 4 ml ofappropriate scintillation fluid (e.g. Picofluor ®15) are added. Aftershaking for 1 h and storage 2 h in the dark the content of radioactivityis determined by liquid scintillation counting. Uptake is obtained bysubtracting the nonspecific binding and passive transport measured inthe presence of 10 μM citalopram (Lu 10-171-B).

For determination of the inhibition of uptake five concentrations ofdrugs covering 3 decades are used.

The measured cpm are plotted against drug concentration onsemilogarithmic paper, and the best fitting s-shaped curve is drawn. TheIC₅₀ -value is determined as the concentration, at which the uptake is50% of the total uptake in control samples minus the nonspecific bindingand uptake in the presence of 10 μM of citalopram.

                  TABLE 1                                                         ______________________________________                                        PHARMACOLOGICAL TEST RESULTS                                                  ______________________________________                                                    5-HTP pot.    5-HT uptake inhibition                              Compound    ED.sub.50 μmol/kg                                                                        IC.sub.50 (nM)                                      ______________________________________                                        (+)-citalopram                                                                            2.0           1.1                                                 (-)-citalopram                                                                            120           150                                                 (±)-citalopram                                                                         3.3           1.8                                                 ______________________________________                                    

(+)-1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile((+)-citalopram) and the non-toxic acid addition salts thereof may beadministered to animals such as dogs, cats, horses, sheeps or the like,including human beings, both orally and parenterally, and may be usedfor example in the form of tablets, .[.capsles.]..Iadd.capsules.Iaddend., powders, syrups or in the form of the usual.[.sterial.]. .Iadd.sterile .Iaddend.solutions for injection. .[.Resultsupon administration to human being have been very gratifying..].

Most conveniently the compounds of Formula I are administered orally inunit dosage form such as tablets or capsules, each dosage unitcontaining the free amine or a non-toxic acid addition salt of one ofthe said compounds in .[.a.]. .Iadd.an .Iaddend.amount of from about0.10 to about 100 mg, most preferably, however, from about b 5 to 50 mg,calculated as the free amine, the total daily dosage usually rangingfrom about 1.0 to about 500 mg. The exact individual dosages as well asdaily dosages in a particular case will, of course, be determinedaccording to established medical principles under the direction of aphysician.

When preparing tablets, the .[.acitve.]. .Iadd.active.Iaddend.ingredient is for the most part mixed with ordinary tabletadjuvants such as corn starch, potato starch, talcum, magnesiumstearate, gelative, lactose, gums, or the like.

Typical examples of formulas for .[.composition.]. .Iadd.compositions.Iaddend.containing (+)-citalopram in the form of an acid addition saltas the active ingredient, are as follows:

    ______________________________________                                        (1) Tablets containing 5 milligrams of (+)-citalopram                         calculated as the free base:                                                  Compound 20                 5      mg                                         Lactose                     18     mg                                         Potato starch               27     mg                                         Saccharose                  58     mg                                         Sorbitol                    3      mg                                         Talcum                      5      mg                                         Gelatine                    2      mg                                         Povidone                    1      mg                                         Magnesium stearate          0.5    mg                                         (2) Tablets containing 50 milligrams of (+)-citalopram                        calculated as the free base:                                                  (+)-citalopram              50     mg                                         Lactose                     16     mg                                         Potato starch               45     mg                                         Saccharose                  106    mg                                         Sorbitol                    6      mg                                         Talcum                      9      mg                                         Gelatine                    4      mg                                         Povidone                    3      mg                                         Magnesium stearate          0.6    mg                                         (3) Syrup containing per milliliter:                                          (+)-citalopram              10     mg                                         Sorbitol                    500    mg                                         Tragacanth                  7      mg                                         Glycerol                    50     mg                                         Methyl-paraben              1      mg                                         Propyl-paraben              0.1    mg                                         Ethanol                     0.005  ml                                         Water ad                    1      ml                                         (4) Solution for injection containing per milliliter:                         (+)-citalopram              50     mg                                         Acetic acid                 17.9   mg                                         Sterile water ad            1      ml                                         (5) Solution for injection containing per milliliter:                         (+)-citalopram              10     mg                                         Sorbitol                    42.9   mg                                         Acetic acid                 0.63   mg                                         Sodium hydroxide            22     mg                                         Sterile water ad            1      ml                                         ______________________________________                                    

Any other pharmaceutical tableting adjuvants may be used provided thatthey are compatible with the active ingredient, and additionalcompositions and dosage forms may be similar to those presently used forneuroleptics, analgesics or antidepressants.

Also combinations of (+)-citalopram as well as its non-toxic acid saltswith other active ingredients, especially other neuroleptics,thymoleptics, tranquilizers, analgetics or the like, fall within thescope of the present invention.

As previously stated, when isolating the enantiomers of citalopram inthe form of an acid addition salt the acid is preferably selected so asto contain an anion which is non-toxic and pharmacologically acceptable,at least in usual therapeutic doses. Representative salts which areincluded in this preferred group are the hydrochlorides, hydrobromides,sulphates, acetates, phosphates, nitrates, methanesulphonates,ethane-sulphonates, lactates, citrates, tartrates or bitartrates,pamoates and maleates of the amines of Formula I. Other acids arelikewise suitable and may be employed if desired. For example: fumaric,benzoic, ascorbic, succinic, salicylic, bismethylenesalicylic,propionic, gluconic, malic, malonic, mandelic, .[.cannamic.]..Iadd.cinnamic.Iaddend., citraconic, stearic, palmitic, itaconic,glycolic, benzenesulphonic, and sulphamic acids may .[.be .]. also beemployed as acid addition salt-forming acids.

When it is desired to isolate a compound of the invention in the form ofthe free base, this may be done according to conventional procedure asby dissolving the isolated or unisolated salt in water, treating with asuitable alkaline material, extracting the liberated free base with asuitable organic .[.solvent.]. .Iadd.solvent,.Iaddend.drying the extractand evaporating to dryness or fractionally distilling to effectisolation of the free basic amine.

The invention also comprises a method for the alleviation, palliation,mitigation or inhibition of the manifestations of certainphysiological-psychological .[.abnormalies.]. .Iadd.abnormalities.Iaddend.of animals, especially depressions.Iadd., .Iaddend.byadministering to a living animal body, including human beings, anadequate quantity of (+)-citalopram or a non-toxic acid addition saltthereof. An adequate quantity would be from about 0.001 mg to about 10mg per kg of body weight in each unit dosage, and from about 0.003milligrams to about 7 milligrams/kg of body weight per day.

It is to be understood that the invention is not limited to the exactdetails of operation or exact .[.compound.]. .Iadd.compounds .Iaddend.orcompositions shown and described, as obvious modifications andequivalents will be apparent to one skilled in the art.

We claim:
 1. A compound selected from substantially pure(+)-1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile and non-toxic acidaddition salts thereof.
 2. A compound of claim 1 being .Iadd.the.Iaddend.pamoic acid salt of substantially pure(+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile.3. A pharmaceutical composition in unit dosage form comprising apharmaceutically acceptable diluent or adjuvant and, as an activeingredient, a compound as defined in claim
 1. 4. A pharmaceuticalcomposition in unit dosage form comprising a pharmaceutically acceptablediluent or adjuvant and, as an active ingredient, the compound of claim2.
 5. A pharmaceutical composition in unit dosage form, according toclaim 3, wherein the active ingredient is present in an amount from 0.1to 100 milligram per unit dose.
 6. A pharmaceutical composition in unitdosage form, according to claim 4, wherein the active ingredient ispresent in an amount from 0.1 to 100 milligram per unit dose.
 7. Amethod for the alleviation of depression in a living animal body subjectthereto which comprises the step of administering to the living animalbody an amount of a compound of claim 1 which is effective for saidpurpose.
 8. A method for the alleviation of depression in a livinganimal body subject thereto which comprises the step of administering tothe living animal body an amount of a compound of claim 2 which iseffective for said purpose.
 9. Method of claim .[.10.]. .Iadd.7.Iaddend.wherein the compound is administered in the form of apharmaceutical composition thereof.
 10. Method of claim 8 wherein thecompound is administered in the form of a pharmaceutical compositionthereof.
 11. A method for the preparation of a compound as defined inclaim 1, which comprises, converting substantially, pure.[.(+)-4-(4-dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)-benzonitrile.]..Iadd.(-)-4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile.Iaddend.or a .[.monomester.]. .Iadd.monoester .Iaddend.thereof in astereoselective way to substantially pure(+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrilewhich is isolated as such or as a non-toxic acid addition salt thereof.12. A compound of the formula .Iadd.(31)-Enantiomer of the compound4-[4-(dimethylamino)-1-(4'-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrileor an ester of said (-)enantiomer, which has the formula .Iaddend.##STR6## wherein R is hydrogen or represents a group completing a labileester.